Uncovering molecular mechanism of hyoid arch deficiencies in ciliopathies

Active Project Grant Awarded Last action

Award ID
F31DE036078
Recipient
Awarding agency
Obligated
$43,855

Award facts

Assistance listing
93.121 Oral Diseases and Disorders Research
Completion date 0% complete
Place of performance
Cincinnati, OH 45229, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The second pharyngeal arch (PA2) derives the facial nerve (CN VII), muscles, and skeletal elements of the tongue, throat, and middle ear. Several ciliopathies, a class of diseases caused by disruptions in the form or function of the primary cilium, a semi-ubiquitous microtubule-based organelle, present with phenotypes indicative of impaired PA2 development, including deafness, glossal deformities, dysarthria, and sleep apnea. While pathogenic mechanisms affecting the development of the first PA (deriving the mandible and maxilla) and third/fourth PA (deriving the laryngeal cartilages) have been characterized in ciliopathies, the mechanisms affecting the development of PA2 have not been studied. To understand the mechanisms of pathogenesis, the TALPID2 (TA2), a bona fide avian model for the human ciliopathy orofaciodigital syndrome subtype 14 (OFD14), and human induced pluripotent stem cells (ipscs) with OFD14-causing variants will be used. The TA2 has impaired sonic hedgehog (SHH) signaling due to aberrant processing of nascent GLI proteins into activator (glia) or repressor (glir) isoforms. Furthermore, preliminary quantitative measurements and micro-CT analysis revealed significant and specific reduction in the size of PA2 in addition to a severe disruption in both morphology and calcification of PA2-derived skeletal elements in TA2 embryos. This proposal tests the hypothesis that aberrant PA2 development in the TA2 is due to disruptions in the establishment of SHH/GLI-mediated signaling centers and/or patterning. Further, we propose that the mechanisms underlying OFD14 pathology are conserved between TA2 and human. In aim 1, we will determine whether SHH signaling centers required for PA2 development are properly established and functional. Further, we will attempt to rescue PA2 hypoplasia via grafting control signaling centers into TA2 embryos. In aim 2, we will determine if GLI-mediated patterning is disrupted in the TA2 using gene expression analysis and GLI3 cut & run. In aim 3, we will determine if pathogenic cellular mechanisms identified in TA2 embryos (SHH/GLI signaling, cell migration) are conserved in human ipscs carrying OFD14 causing variants. This proposal will elucidate the mechanism of disrupted PA development in ciliopathies, revealing novel mechanisms that could be targeted in human OFD14 patients. The proposed training will take place in cincinnati children's research foundation, a tier-one research institution, ranked the #1 children's hospital in 2023. The training plan includes technical trainings in biochemical assays (cut & run) and bioinformatic analysis, advanced human ipsc experimental techniques, advanced manipulation of the avian embryo, mastery of writing and presenting scientific research, mentoring and leadership skills, and physician- scientist career development.

Quick answers

Who received award F31DE036078?

F31DE036078 was awarded to Childrens Hospital Medical Center by National Institute of Dental and Craniofacial Research (National Institutes of Health) on March 3, 2027.

How much is award F31DE036078 worth?

$43,855 has been obligated on F31DE036078.

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